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342 > regulation of gpcr signalling > Flashcards

regulation of gpcr signalling Flashcards

be able to write out the pathways n shit here e.g. in an essay

1
Q

what are GPCRs

A

g protein coupled receptors
largest receptor family
can be tissue specific
polypeptide chain of 300-500 amino acids

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2
Q

GPCRs are the largest receptor family with ____ members

A

> 800

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3
Q

approximately 500 GPCRs are expressed in ____ tissues

A

olfactory - sense of smell
(example of tissue specific)

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4
Q

___ to ___% of drugs in the market target GPCRs

A

30 - 50%

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5
Q

what are GPCRs characterised by (4)

A

7 transmembrane domains of alpha helices - largest family of membrane spanning receptors

distinctive structure

extracellular N terminus

intracellular C terminus

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6
Q

what shape does the transmembrane of a GCPR form and what does it contain

A

barrel - contains ligand binding site for ligand to bind to and activate

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7
Q

what are G proteins

A

heterotrimeric proteins of alpha, beta, gamma subunits

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8
Q

what does ligand binding in GPCRs cause

A

conformation change, leading to receptor acting as a guanine nucleotide exchange factor (GEF)

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9
Q

what is the role of GTP in GPCRs

A

GTP activates the G protein and causes dissasociation of the Ga G alpha subunit from the beta gamma subunit

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10
Q

what is the role of guanine nucleotide exchange factor GEF in GPCRs

A

loads G protein with GTP, which activates it

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11
Q

there are distinct Ga subunits that have different signal transduction through second messagers. true or false?

A

true

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12
Q

what is the signal transduction pathway of G alpha s (Gs) / stimulatory G alpha subunit

A

positive effect on adenylate cyclase

inc cyclic AMP (cAMP)

inc activation protein kinase A (PKA)

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13
Q

what is the signal transduction pathway of G alpha i (Gi) / stimulatory G alpha subunit

A

negative effect on adenylate cyclase

dec cyclic AMP (cAMP)

dec protein kinase A (PKA)

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14
Q

what is the signal transduction pathway of G alpha 12/13 (G12/13) / stimulatory G alpha subunit

A

activates Rac/Rho protein (a GTPase protein)

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15
Q

what is the signal transduction pathway of G alpha q (Gq) / stimulatory G alpha subunit

A

interacts with PLC phospholipase C which

converts PIP2= Phosphatidylinositol 4,5-bisphosphate

to IP3 = inositoltriphosphate and
DAG = diacylglycerol

IP3 inc PKC = Protein kinase C

inc Calcium ions leading to

activates CamKII = calmoduline-dependent kinase II

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15
Q

what do second messengers do

A

amplify signal

ie 1 mol activates GPCR, activates 1000 mols, downstream effects to 100,000 mol

e.g. Gi

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15
Q

GPCR signalling is not only determined by agonist binding, but is also ____ ____ by interactions with other receptors

A

allosterically modulated

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15
Q

some GCPRs dimerise when activated - what are these called and what do they mean (2)

A

homodimer - same GCPR
heteromers - different GCPR

type of dimer will impact GPCR signalling downstream

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15
Q

what are bivalent ligands

A

2 bound ligands that activate both GPCR heteromers
(each binds to GPCR, then form dimer, then other binds for third different effect)

aka form new ligand, only activates certain receptors if they are bivalent (stuck together in heterodimer)

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15
Q

receptor dimerisation is common in other types of receptors such as ___ ___ but remains controversial in the GPCR

A

tyrosine kinases

we are beginning to generate ligands that can activate both receptors in a dimer pair e.g. bivalent ligands

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16
Q

risk of cell signalling if not controlled

A

pathogenic signalling causing disease tumourogenisis

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17
Q

example of effect of pathogenic signalling

A

tumourogenisis, cancers

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18
Q

how to avoid pathogenic signalling

A

changing sensitivity of receptors can be adjusted based on levels of stimulation
(GPCR desensitisation)

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19
Q

changing sensitivity of receptors can be adjusted based on levels of stimulation. what is an example of this

A

rhodopsin is a GPCR in the rods of the retina - in very bright and dark light, sensitivity of receptors change - this is GPCR re/desensitising

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20
Q

what is GPCR desensitisation

A

waning/ reduction of cellular response in the face of continued or repeated stimulation - e.g. light
ie agonist response decreases

also conserves ATP

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21
Q

what is homologous desensitisation

A

the receptor only becomes desensitised to a specific agonist and normal response returns when a different agonist is used

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22
Q

what is heterologous desensitisation

A

receptor becomes desensitised to any agonist

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23
Q

how does activation of GPCRs reduce GPCR activation at a later time (8)

A

add agonist, activate GPCR

GPCR activation activates second messenger systems (e.g. cAMP) including PKA protein kinase

kinases phosphorylate proteins e.g. the activated GPCR when the G protein heteromer is dissociated (or coupled to G protein)

the newly phosphorylated sites on the GPCR cannot reassociate the G protein heteromer

this causes uncoupling of G protein from GPCR

the second messenger no longer promotes signal transduction from the receptor as ligand is less bound to GPCR

beta arrestin is recruited to replace G protein heteromer, blocks G protein heteromer blocking cell signalling

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24
Q

what do protein kinases do

A

phosphorylate proteins

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25
Q

example of a protein kinase

A

PKA

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26
Q

what does beta arrestin do (2)

A

block G protein heteromer by replacing it and binding to GPCR once it dissociates

inhibits downstream signalling transduction when interacts with GCPR aka signalling desensitisation

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27
Q

how do we know beta arrestin replaces G protein heteromer

A

we genetically engineer and attach green fluorescent protein (GFP) to beta arrestin

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28
Q

affect on beta-arrestin when receptor agonists e.g. isoproterenol is administered

A

forms clusters at cell membrane to bind to GPCR- moves away from defuse localisation translocates to membrane

shown as fluoresence

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29
Q

receptor agonist example

A

isoproterenol

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30
Q

the structure of beta arrestin suggests it is able to interact with proteins such as ___ and ___

A

clathrin
AP2

31
Q

what are clathrin and AP2 involved in

A

endocytosis of receptors from cell membrane into cell to be altered and resensitised

means over time the receptor will gain sensitivity

32
Q

how does clathrin and AP2 work

A

endocytic

these proteins bind and remove receptor from membrane

membrane invaginates

receptor eventually removed from EC facing environment

invagination eventually forms a vesicle containing GCPR - no longer on membrane

clathrin coated vesicle

eventually uncoats and forms early endosome

receptors dephosphorylate and recycle back to cell membrane to signal anew

GPCR no longer phosphorylated so G protein can recouple and GPCR is resensitised, transduction can occur

33
Q

what is clathrin (4)

A

structural molecule
complex of light chain and heavy chain/ 2 proteins
3 legged structure/ trimeric
self form in cells as a lattice of hexagones, allows to bend membrane/ internalisations

34
Q

what other outcome can occur for an early endosome (5):

A

downregulation:

GCPR as early endosome sent for degradation and broken down

results less receptors avaliable for signalling
receptor downregulation

long term, is why patients/addicts can present with drug tolerance - less receptors so inc dose needed

receptor signalling cannot recover when agonist present until new synthesis of receptor occurs

35
Q

what is early endosome degradation caused by

A

lysosome

36
Q

how does a degraded early endosome recover

A

receptor signalling cannot recover when agonist present until new synthesis of receptor occurs via transcription/ translation - cannot reuse
agonist should be removed also

37
Q

beta arrestin is also a ____ ____

A

signal transducer - arrestin mediated signalling

38
Q

what can beta arrestin activate

A

sarcoma (Src)

by accumulating clathrin coated vesicles

39
Q

what is sarcoma (Src) used for

A

activates MAPK MAPkinase signalling pathway - cell growth, proliferation

40
Q

what is the MAPK pathway also known as

A

Ras-Raf-MEK-ERK pathway
(each protein phosphorylates protein that comes after)

41
Q

in the MAPK pathway, what is the function of ERK

A

translocates to nucleus and trigger transcription and translation

42
Q

what, other than beta arrestin, can activate the MAPK pathway aka is a signal transducing protein unit

A

G protein beta gamma subunit

exact mechanism varies depending on cell type - can activate through Src or directly Ras

43
Q

what can activate the PI-3 Kinase (PI3K) pathway

A

G protein beta gamma subunit

44
Q

what does the PI-3 Kinase (PI3K) pathway activate

A

PKB/Akt

45
Q

what does PKB/Akt do

A

inhibit apoptotic processes, contributing to cellular survival pathways

relevant to cancer – upregulated in cancer

46
Q

what can activate ionotropic channels on cell membrane e.g. calcium ions from EC environment to IC environment or potassium ions from IC to EC

A

beta gamma subunit

47
Q

what is an ionotrophic channel

A

undergoes conformational change when activated and allow ions to flow through

48
Q

two ways GPCR signalling originates from

A

1- G protein signalling response mediated from alpha subunit and beta-gamma subunits

2- beta-arrestin signalling response, can produce distinct pathways not present in G alpha signalling pathways (1st option)

49
Q

what is biased GPCR signalling

aka signalling bias

A

biased agonists can activate one signalling pathway over another (G protein signalling vs beta arresting signalling response)

50
Q

example of biased agonist

A

oliceridine - opioid med

51
Q

what does oliceridine act as an agonist for and what does it activate

A

biased agonist for mu opioid receptor

preferentially activates G protein signalling over beta arrestin signalling

52
Q

effect of oliceridine in terms of drug tolerance

A

reduced beta arrestin recruitment

less receptor internalisation

reduced likelihood of drug tolerance as drug does not go through desensitisation or downregulation

common with drugs e.g. morphine that bind to mu opioid receptors

53
Q

what do GCPRs transduce

A

signal from wide range of extracellular ligands

54
Q

examples of extracellular ligands that GCPRs transduce

A

light, calcium ions, odorants, small molecules, proteins

55
Q

is the GCPR N terminus intra or extracellular

A

extracellular

56
Q

is the GCPR C terminus intra or extra cellular

A

intracellular

57
Q

how are GCPRs activated

A

ligand binds

58
Q

what is downstream signalling

A

also known as signal transduction pathways, are the processes that control how cells respond to signals and drive their overall activity

59
Q

what is the most pharmacologically relevant heterotrimeric protein of G proteins

A

alpha (Ga) is the most pharmacologically relevant

60
Q

what is GEF

A

guanine nucleotide exchange factor (GEF)

61
Q

how is GTP activated

A

GEF guanine nucleotide exchange factor

displaces GDP and loads on GTP

62
Q

the recruitment of beta arrestin requires

A

phosphorylation from PKA

if PKA null cell, no beta arrestin aka no clusters, diffused expression

63
Q

what is resensitisation

A

recovery of cell responsiveness via endocytosis after desensitisation

then, can be resensitised
through dephosphorylation through protein phosphates like PP2A

and recycled back to cell membrane

64
Q

When an RTK is activated it will form a dimer with another RTK. It will then ___________ the dimer partner to allow for adaptor proteins to bind.

A

transphosphorylate

65
Q

Activation of PI3K by RTKs results in downstream signaling which activates which protein?

A

PKB

66
Q

Receptor downregulation can be overcome by ______________.

A

Removing agonist and allowing new synthesis

67
Q

class A GPCRs

A

interact with ligands in the EC

68
Q

class B GPCRs

A

interact with peptides

69
Q

class C GPCRs

A

are dimers

70
Q

subunit G ____ allows for drug receptor complex specificity

A

alpha

as it is variable

71
Q

what occurs in the intracellular C terminus when the GPCR binds

A

undergoes conformational change causing high affinity to the G protein

72
Q

what anchors the GPCR

A

the beta gamma subunit

73
Q

how else can amplification occur

A

freed active receptors can bind to other G proteins

74
Q

cholera toxin

A

activates Gs singalling pathway via ADP-ribosylation of Gas subunit

dissociates Gas subunit from beta gamma subunit

activates adenylyl cyclase

inc cAMP excessively

inc PKA

phosphorylates/ opens ions channels in intestinal epithelium

inc flow of ions into intestine lumen

osmosis into lumen

profuse diarrhoea/ dehydration

aka cholera

75
Q

carvediol

A

beta-adrenergic receptor blocker

signalling bias for beta-arrestin mediated signalling

clinically used for treating chronic heart failure

76
Q

what is the difference between desensitisation and downregulation

A

desensitisation is a temporary reduction while downregulation is a long term decrease

desensitisation prevents overstimulation due to excessive signalling and loss of energy
downregulation leads to inc tolerance

77
Q

what is a GRK

A

G-protein-coupled receptor kinase

phosphorylate activated GPCRs, marking for desensitisation

78
Q

what two factors contribute to desensitisation

A

GRKs - account for some reduced signalling as leads to reduced interaction with G-protein

β-arrestin recruitment - accounts for most of desensitisation as outcompetes G-proteins

79
Q

how were β-arrestins discovered

A

it was seen that β-arrestins prevented coupling of phosphorylated rhodopsin to the G-protein transducin

proved that β-arrestins do not readily dissociate, but G-proteins do

80
Q

β-arrestin mutations

A

β-arrestins can be mutated to engage only one receptor site, leaving the other free to bind with the G protein, resulting in simoultaneous interaction

81
Q

what type of desensitisation does salbutamol cause

A

homologous

B2 adrenergic receptor post exposure to salbutamol agonist

82
Q

where do clathrin and AP2 bind

A

C termini

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